Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by the central and peripheral nervous systems and by endocrine cells. CGRP exerts diverse biological effects on the cardiovascular, gastrointesti-nal, respiratory, central nervous and immune systems. Little is known, however, about the molecular mechanisms that mediate CGRP effects. Using the NF k B-lucif-erase reporter transgenic mice, here we show that CGRP selectively inhibits NF- k B-mediated transcription in thymocytes in vitro and in vivo . In contrast, CGRP does not affect transcription mediated by the AP-1 and NFAT transcription factors. CGRP inhibits the accumulation of NF- k B complexes in the nucleus by preventing phosphorylation and degradation of the NF- k B inhibitor I k B. Inhibition of NF- k B activity is associated with the induction of apoptosis by CGRP